Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Hemophilia is the X-linked bleeding disorder caused by mutations in coagulation factor IX (FIX, hemophilia B) or its co-factor, factor VIII (FVIII, hemophilia A). Since the serine protease FIX has very low activity in the absence of FVIII, mutations in either protein can cause the coagulation defect. Hemophilia A disease affects 1 in 7,500 male births worldwide, whereas hemophilia B affects 1 in 30,000.1-3 Hence, the majority of hemophilia patients are FVIII-deficient. Current standard treatment is based on intravenous (IV) infusion of plasma-derived or recombinant factor concentrate. A major complication of this therapy is the formation of inhibitory antibodies (“inhibitors”), which occurs in 20-30% of patients with severe hemophilia A (as defined by <1% coagulation activity) and in ˜5% of severe hemophilia B patients.1,4-6 Inhibitors seriously complicate treatment and increase morbidity and mortality of this disease. Increased factor doses may be able to restore hemostasis in patients with low-titer inhibitors (<5 Bethesda Units, BU), while bypass factors are required to treat a bleed in the presence of high-titer inhibitors. However, these treatments are expensive and have to be carefully dosed. Clinical protocols for reversal of the antibody response via immune tolerance induction (ITI) consist of frequent high-dose factor administrations for prolonged periods (months to >1 year), are very expensive (>$1,000,000), and ˜30% of FVIII inhibitor patients fail to respond.4 
While the overall incidence of inhibitors is lower in hemophilia B (1-4%), 9-23% of patients with severe disease form inhibitors. These are typically high-titer and are almost exclusively confined to subjects with gene deletions or early stop codons. ITI protocols are less effective for treatment of inhibitors to coagulation factor IX (F.IX). Importantly, studies found that up to 50% of patients with F.IX inhibitors may experience potentially life-threatening anaphylactic reactions to F.IX, which also preclude the subject from home treatment and severely hinder ITI protocols.